Fibroblast Growth Factor Receptors
Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate fundamental developmental pathways and are expressed in a wide variety of tissues. FGFs stimulate proliferation, cell migration, differentiation, and play a major role in skeletal and limb development, wound healing, tissue repair, hematopoiesis, angiogenesis, and tumorigenesis (see, e.g., Turner and Crose, Nature Reviews Cancer 10: 116-129 (2010)).
The mammalian FGF family comprises many ligands, which exert their actions through four highly conserved transmembrane tyrosine kinase receptors, FGFR1, FGFR2, FGFR3, and FGFR4. A typical FGFR has a signal peptide that is cleaved off, three immunoglobulin (Ig)-like domains (Ig domain I, II and III), an acidic box, a transmembrane domain, and a split tyrosine kinase domain (see, e.g., Ullrich and Schlessinger, Cell 61: 203 (1990); Johnson and Williams, Adv. Cancer Res. 60:1-41 (1992)).
Additionally, alternative splicing of the transcribed receptor genes results in a variety of receptor isoforms, including soluble, secreted FGFRs, FGFRs with truncated COOH-terminal domain, FGFRs with either two or three Ig-like domains, as well as FGFR isoforms arising via alternative splicing of the third Ig-like domain occurs only for FGFR1, FGFR2, and FGFR3 and specifies the second half of the third Ig-like domain, resulting in either the Mb or the IIIc isoform of the receptor. The 2nd and the 3rd Ig-like domains of the receptors are necessary and sufficient for ligand binding, whereas the first Ig-like domain is thought to play a role in receptor autoinhibition. Thus, the different receptors and their isoforms display different ligand-binding specificities (see, e.g., Haugsten et al., Mol. Cancer. Res. 8:1439-1452 (2010)).
The FGFs can also bind to heparin sulfate proteoglycans (HSPG), besides binding to distinct FGFRs and their splice variants. Thereby a dimeric FGF-FGFR-HSPG ternary complex forms on the cell surface. The ternary complex is stabilized by multiple interactions between the different components in the complex. Two FGF-binding sites, a heparin-binding site, and a receptor-receptor interaction site have been identified within the Ig-like domains II and III of the receptor. (Haugsten et al., 2010).
Binding of FGFs to FGFRs induces receptor dimerization, which enables transphosphorylation of a tyrosine in the activation loop of the kinase domain. The active FGFRs have been shown to phosphorylate multiple intracellular proteins such as FRS2, and PLCγ (Eswarakumar et al., Cytokine Growth Factor Rev 16:139-149 (2005)). FGFR signaling produces distinct biological responses in different cell types, ranging from stimulation of cell proliferation and survival to growth arrest, migration, and differentiation.
FGFRs and Cancer
FGF signaling mediates a powerful combination of effects: self-sufficiency in growth/survival, neoangiogenesis and tumor cell migration. Consequently, FGF signaling has the potential of being strongly oncogenic once the tight regulation exerted on its physiological functions is lost (see, e.g., Heinzle et al., Expert Opin. Ther. Targets 15(7):829-846 (2011)).
Gene amplification and/or overexpression of FGFR1, FGFR2 and FGFR4 has been implicated in breast cancer (Penault-Llorca et al., Int J Cancer 1995; Theillet et al., Genes Chrom. Cancer 1993; Adnane et al., Oncogene 1991; Jaakola et al., Int J Cancer 1993; Yamada et al., Neuro Res 2002). Overexpression of FGFR1 and FGFR4 is also associated with pancreatic adenocarcinomas and astrocytomas (Kobrin et al., Cancer Research 1993; Yamanaka et al., Cancer Research 1993; Shah et al., Oncogene 2002; Yamaguchi et al., PNAS 1994; Yamada et al., Neuro Res 2002). Prostate cancer has also been related to FGFR1 overexpression (Giri et al., Clin Cancer Res 1999).
In general FGFR2 and FGFR1 are more commonly deregulated by gene amplification. In gastric cancer, an amplified FGFR2 gene is associated with poor prognosis (Kunii et al., Cancer Res. 68:2340-2348 (2008)). A FGFR2-IIIb to Inc switch can also be a sign of tumor progression, epithelial-mesenchymal transition and high invasiveness in bladder and prostate cancers. Switching in this case substitutes a Mb receptor variant that exerts anti-tumorigenic activity with a protumorigenic Inc receptor (see, e.g., Heinzle et al., 2011). So far FGFR2 mutations have been implicated in skin, endometrial, ovary, and lung cancer. FGFR4 mutations have been implicated in rhabdomyosarcoma, lung, and breast cancer (see, e.g., Heinzle et al., 2011).
Antibody Drug Conjugates
Antibody drug conjugates (“ADCs”) have been used for the local delivery of cytotoxic agents in the treatment of cancer (see e.g., Lambert, Cuff. Opinion In Pharmacology 5:543-549, 2005). ADCs allow targeted delivery of the drug moiety where maximum efficacy with minimal toxicity may be achieved. As more ADCs show promising clinical results, there is an increased need to develop new therapeutics for cancer therapy.